method for manufacturing a pharmaceutical composition for controlled release of an active substance

ABSTRACT

The present invention pertains to a sized product, which contains a drug, polyethylene oxide with a molecular weight of 2,000,000 or higher, and a specific size controlling agent for polyethylene oxide (substance with the appropriate plasticity and binding force) and wherein at least the above-mentioned specific size controlling agent is uniformly dispersed in the above-mentioned polyethylene oxide, a controlled-release pharmaceutical composition containing this sized product, and a method of manufacturing a controlled-release pharmaceutical composition containing this sized product. 
     A controlled-release pharmaceutical composition with good uniformity of content can be presented by using powder particles of polyethylene oxide with powder properties suitable for tableting, which is obtained by uniform dispersion of the specific size controlling agent for polyethylene oxide of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application claiming priorityto U.S. patent application Ser. No. 10/746,562 filed Dec. 23, 2003,allowed, which application claims the benefit of priority of U.S. PatentApplication No. 60/453,046, filed Mar. 6, 2003, the disclosures of eachapplication are hereby incorporated by reference in their entirety forall purposes.

FIELD OF THE INVENTION

The present invention pertains to a pharmaceutical composition forcontrolled release, which comprises a drug, polyethylene oxide with amolecular weight of 2,000,000 or higher, and a specific size controllingagent for the above-mentioned polyethylene oxide and wherein theabove-mentioned drug and above-mentioned specific size controlling agentare uniformly dispersed in the above-mentioned polyethylene oxide.Moreover, the present invention pertains to a method of manufacturingthis controlled-release pharmaceutical composition as well as acontrolled-release pharmaceutical preparation comprising particles ofthis controlled-release pharmaceutical composition.

BACKGROUND OF THE INVENTION

Sustained-release pharmaceutical preparations are developed for thepurpose of improving compliance as a result of reducing the number oftimes they are administered or preventing adverse reaction by making theblood concentration fluctuations (peak/trough) smaller and therebyrealizing stable therapeutic results, and various pharmaceuticalpreparations have been developed in recent years. Varioussustained-release pharmaceutical preparations have been created by thepresent applicant as well. Of these, hydrogel sustained-releasepharmaceutical preparations comprising a hydrophilic base (also gelationenhancer hereafter) and hydrogel-forming polymer can be easilymanufactured because the composition and components are simple. Thissustained-release pharmaceutical preparation can release a drug in theupper digestive tract, including the stomach and the small intestine, aswell as the lower digestive tract, including the colon. In other words,the entire digestive tract can be used as the site of absorption.Therefore, it is highly practical and very useful as a pharmaceuticalpreparation with small inter-subject variation in terms of drugabsorption in humans (for instance, refer to Patent Reference 1:International Publication Pamphlet No. 94/06414).

The inventors of inventions relating to the above-mentionedsustained-release pharmaceutical preparations proposed various polymersas hydrogel-forming polymers, but of these, polyethylene oxide iscapable of imparting particularly good controlled-release performance tothe pharmaceutical preparation and therefore, polyethylene oxide isusually selected as the polymer of first choice for the hydrogel-formingpolymer. However, polyethylene oxide is a water-soluble thermoplasticresin in the form of a white powder or granules whose molecular weightreaches several 100,000 to several 1,000,000 that is obtained bypolymerization of ethylene oxide, and polyethylene oxide with amolecular weight of 2,000,000 or higher becomes very sticky when exposedto moisture. Therefore, when water is added to polyethylene oxide orpolyethylene oxide is handled under high humidity, it shows a very highviscosity, and polyethylene oxide can therefore be perceived as asubstance that is difficult to handle during each process ofpulverization, granulation, tableting, and the like, particularly duringgranulation. Therefore, methods have been presented in the past,including wet granulation, whereby for example, a chloride solvent suchas dichloromethane or carbon tetrachloride or an alcohol solvent such asmethanol, ethanol, or propanol is used alone or as a mixture with waterdirect tableting, and dry granulation when sustained-releasepharmaceutical preparations that use polyethylene oxide, particularlymatrix-type controlled-release pharmaceutical preparations that containpolyethylene oxide as the controlled-release base, contain a highconcentration of polyethylene oxide with a high viscosity, (forinstance, refer to Patent Reference 1: International PublicationPamphlet No. 94/06414, Patent Reference 2: International PublicationPamphlet No. 01/10466, Patent Reference 3: Specification of U.S. Pat.No. 5,273,758).

In addition, there is also a method of producing a pharmaceuticalpreparation by spray granulation of tablet starting materials comprisingpolyethylene oxide with a molecular weight of 100,000 using an aqueoushydroxypropylmethyl cellulose solution (Patent Reference 4:Specification of U.S. Pat. No. 4,662,880, Patent Reference 5:Specification of U.S. Pat. No. 4,810,502 (corresponds to Japanese KokaiPatent No. Hei 7-215869)). Although the conditions of wet granulation,and the like, are not entered to such an extent that granulation can beconducted by persons in the field, polyethylene oxide with a molecularweight of 2,000,000 or higher has a viscosity of 2,000 mPa·s or higher(millipascal second: aqueous 2% w/v solution, 25° C.) and this viscosityis dramatically higher than the viscosity of polyethylene oxide with amolecular weight of 100,000 of 30 to 50 mPa·s (aqueous 5% w/v solution,25° C.). Therefore, it appears that when the same wet granulation methodis used, granulation proceeds too far or a powder the particles of whichbecome thread-like in appearance is produced and a powder that isappropriate for tableting cannot be made in that powder particles withpoor fluidity are produced, and the like.

Furthermore, it goes without saying that when a controlled-releasepharmaceutical preparation containing a low dose of drug is made, itmust be made so that the active ingredient is contained uniformly perunit of the pharmaceutical preparation. Nevertheless, there are alsoproblems with direct tableting and dry granulation in that the drug isscattered and the drug content is reduced, or uniformity of drug contentis diminished, and further, productivity is poor because thegranulation/pulverization process is repeated, and the like.

Furthermore, a variety of problems are indicated with wet granulationusing an organic solvent, including environmental pollution, safetyduring manufacture (risk of explosion, and the like), expenditure onmanufacturing facilities (explosion-proof equipment, use of organicsolvents, and recovery facilities), and the like (for instance, refer toPatent Reference 3).

Patent Reference 1:

International Publication Pamphlet No. 94/06414

Patent Reference 2:

International Publication Pamphlet No. 01/10466

Patent Reference 3:

Specification of U.S. Pat. No. 5,273,758

Patent Reference 4:

Specification of U.S. Pat. No. 4,662,880

Patent Reference 5:

Specification of U.S. Pat. No. 4,810,502 (corresponds to Japanese KokaiPatent No. Hei 7[1995]-215869)

Consequently, there is the need today for the presentation of a powderthat is appropriate for tableting in order to manufacture apharmaceutical composition for controlled release of active substancescontaining polyethylene oxide with a molecular weight of 2,000,000 orhigher and having good uniformity of drug content, the presentation of acontrolled-release pharmaceutical composition containing this powder,and the presentation of a method of manufacturing this powder or acontrolled-release pharmaceutical composition containing this powder.

DISCLOSURE OF THE INVENTION

The present inventors knew that many problems are encountered andrealistically, manufacture is difficult during manufacturing a powderfor controlled-release by aqueous system by using polyethylene oxideparticles when the wet granulation method using a conventional binder isemployed. That is, for instance, a powder that is appropriate fortableting cannot be manufactured because various diverse problems areencountered. For instance, when a binder that has binding force butshows poor plasticity, such as PVP, is used, granulation proceeds toofar and powder particles with a high specific volume and poor fluidityare obtained, when a saccharide that has viscosity increasing power andbinding force but becomes thread-like during spray drying, such assorbitol, or a surfactant that has plasticity but shows poor bindingforce, such as polysorbate, is used, a powder with a small particlediameter is produced (the powder further breaks down into very fineparticles) and becomes a powder that has a strong tendency toward beingscattered and therefore, tableting is obstructed, and the like.

Therefore, the present inventors discovered that when a portion of thepolyethylene glycol (also PEG hereafter) that is used as a gelationenhancer (hydrophilic base) of the components of the above-mentionedhydrogel-forming sustained release pharmaceutical preparation is addedto a suspension of the drug and this suspension is sprayed on thepolyethylene oxide, polyethylene oxide with a high viscosity does notbecome thread-like and can be sized into powder that has properties(specific volume, and the like) suitable for tableting. Surprisingly,the inventors discovered that even if a suspension containing a low doseof the drug is sprayed, the controlled-release pharmaceuticalpreparation consisting of this spray-dried product is a pharmaceuticalpreparation with superior uniformity of content.

As a result of further intense studies focusing on polyethylene oxide,the inventors discovered that when polyethylene oxide of a highviscosity and PEG in solid form are used for the fluidized bedgranulator and an aqueous solution of the drug is sprayed on this, apolyethylene oxide sized product showing properties suitable fortableting can be produced, as with the above-mentioned method, and thatsuperior uniformity of content is displayed by the controlled-releasepharmaceutical preparation obtained by tableting this sized product.

Furthermore, the inventors also discovered that powder particles withpolyethylene oxide properties that are appropriate for tableting, and acontrolled-release pharmaceutical preparation with excellent uniformityof content that is obtained by tableting these polyethylene oxide powderparticles are obtained when hydroxypropylmethyl cellulose (also HPMChereafter), hydroxypropyl cellulose (also HPC hereafter) or methylcellulose (also MC hereafter) of a specific viscosity grade is used aswith PEG.

The details of this mechanism are still unclear. The polyethylene oxideproduct itself is a powder that is an aggregate of very fine particlesand when water is used, this is broken down into fine particles, or onthe other hand, marked granulation will proceed. However, it ishypothesized that by selecting and using a specific substance with theappropriate plasticity and binding force, the polyethylene oxideparticles themselves will rebind with the polyethylene oxide powderparticles that have properties appropriate for tableting and thereby besized. The polyethylene oxide powder of the present invention is alsoreferred to hereafter as the polyethylene oxide sized product or simplythe sized product.

The present invention is based on this series of discoveries, presenting

1. a pharmaceutical composition for controlled release comprising asized product, which comprises (a) a drug, (b) polyethylene oxide with aviscosity-average molecular weight of 2,000,000 or more, and (c) a sizecontrolling agent for (b) polyethylene oxide and wherein of said threecomponents, at least size controlling agent (c) is uniformly dispersedin polyethylene oxide (b),

2. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein (c) size controlling agent for (b)polyethylene oxide is one or two or more selected from the groupconsisting of polyethylene glycol that is solid at ordinary temperature,hydroxypropylmethyl cellulose of 2 to 15 mPa·s (2% w/v),hydroxypropylmethyl cellulose of 2 to 10 mPa·s (2% w/v), and methylcellulose of 2 to 15 mPa·s (2% w/v),

3. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein the amount of (c) size controlling agent for(b) polyethylene oxide is 0.5 to 60 wt % per polyethylene oxide (b),

4. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein when polyethylene glycol is selected as (c)size controlling agent for (b) polyethylene oxide, the amount is 0.5 to60 wt % per unit of the pharmaceutical preparation,

5. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein the amount of polyethylene oxide (b) is 10 to95 wt % per unit of the pharmaceutical preparation,

6. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein the amount of polyethylene oxide (b) added isat least 70 mg per unit of the pharmaceutical preparation,

7. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein viscosity-average molecular weight ofpolyethylene oxide (b) is 5,000,000 or higher,

8. a pharmaceutical composition for controlled release according toabove-mentioned 1, which further comprises a hydrophilic base,

9. a pharmaceutical composition for controlled release according toabove-mentioned 8, wherein the amount of water required to dissolve 1 gof the above-mentioned base is 5 ml or less (20±5° C.),

10. a pharmaceutical composition for controlled release according toabove-mentioned 9, wherein the hydrophilic base is polyethylene glycol,sucrose, or polyvinyl pyrrolidone,

11. a pharmaceutical composition for controlled release according toabove-mentioned 8, wherein the amount of hydrophilic base is 5 to 80 wt% per unit of the pharmaceutical preparation,

12. a pharmaceutical composition for controlled release according toabove-mentioned 1 or 8, which further comprises yellow ferric oxideand/or red ferric oxide,

13. a pharmaceutical composition for controlled release according toabove-mentioned 12, wherein the amount of yellow ferric oxide and/orferric oxide is 0.3 to 20 wt % per polyethylene oxide,

14. a pharmaceutical composition for controlled release according toabove-mentioned 1, wherein the amount of drug is 85 wt % or less perunit of the pharmaceutical preparation,

15. a pharmaceutical composition for controlled release according toabove-mentioned 14, wherein the amount of drug is 10 wt % or less perunit of the pharmaceutical preparation,

16. a pharmaceutical composition for controlled release according to anyone of above-mentioned 1 through 15, wherein the drug is tamsulosinhydrochloride,

17. a pharmaceutical composition for controlled release according toabove-mentioned 1, which comprises essentially no organic solvent, and

18. a polyethylene oxide-containing powder for controlled-releasepharmaceutical compositions, which contains polyethylene oxide (b) witha viscosity-average molecular weight of 2,000,000 or higher and (c) asize controlling agent for (b) polyethylene oxide and wherein at leastsize controlling agent (c) is uniformly dispersed in polyethylene oxide(b).

19. a sized product according to claim 18, wherein (c) a sizecontrolling agent for (b) polyethylene oxide is one or two or moreselected from the group consisting of polyethylene glycol that is solidat ordinary temperature, hydroxypropylmethyl cellulose of 2 to 15 mPa·s(2% w/v), hydroxypropylmethyl cellulose of 2 to 10 mPa·s (2% w/v), andmethyl cellulose of 2 to 15 mPa·s (2% w/v),

20. a sized product according to claim 18, wherein the amount of (c) asize controlling agent for (b) polyethylene oxide is 0.5 to 60 wt % perpolyethylene oxide (b),

21. a sized product according to claim 18, wherein when polyethyleneglycol is selected as (c) a size controlling agent for (b) polyethyleneoxide, the amount is 0.5 to 60 wt % per unit of the pharmaceuticalpreparation,

22. a sized product according to claim 18, wherein the amount ofpolyethylene oxide (b) is 10 to 95 wt % per unit of the pharmaceuticalpreparation,

23. a sized product according to claim 18, wherein the amount ofpolyethylene oxide (b) added is at least 70 mg per unit of thepharmaceutical preparation,

24. a sized product according to claim 18, wherein viscosity-averagemolecular weight of polyethylene oxide (b) is 5,000,000 or higher,

25. a sized product according to claim 18, which further comprises ahydrophilic base,

26. a sized product according to claim 25, wherein the amount of waterrequired to dissolve 1 g of said base is 5 ml or less (20±5° C.),

27. a sized product according to claim 26, wherein the hydrophilic baseis polyethylene glycol, sucrose, or polyvinyl pyrrolidone,

28. a sized product according to claim 25, wherein the amount ofhydrophilic base is 5 to 80 wt % per unit of the pharmaceuticalpreparation,

29. a sized product according to any one of claims 18 to 25, whichfurther comprises yellow ferric oxide and/or red ferric oxide,

30. a sized product according to claim 29, wherein the amount of yellowferric oxide and/or ferric oxide is 0.3 to 20 wt % per polyethyleneoxide,

31. a sized product according to claim 18, which further comprises adrug,

32. a sized product according to claim 18 or 31, wherein the amount ofdrug is 85 wt % or less per unit of the pharmaceutical preparation,

33. a sized product according to claim 32, wherein the amount of drug is10 wt % or less per unit of the pharmaceutical preparation,

34. a sized product according to any one of claims 18 through 33,wherein the drug is tamsulosin hydrochloride,

35. a sized product according to claim 18, which comprises essentiallyno organic solvent,

36. a use of a sized product according to any one of claims 18 through35 as a base for controlled-release preparation.

International Publication Pamphlet No. 92/10169 (corresponding toJapanese Patent No. 3239319) describes that the invention relating to amanufacturing method for a sustained-release dosage form for oral use,utilizing hydrophilic matrix gel component as a base, performing byusing aqueous solution containing 20-50% solute, which is selected oneor more from a poly-alcohol or polyvinylpyrrolidone, which is capable ofbecoming gel when administering orally to a mammal such as human,wherein gel-forming component is hydroxypropylmethylcellulose havingvarious kinds of viscosity grade, wherein manufacturing wet-granules ispreventing gelation of hydroxypropylmethylcellulose during granulationprocess. Said pamphlet also describes that wet-granulation by utilizinggranulation in order to make granules obtained by granulation crushableas a granulation method for HPMC. However, the present invention is nota technology relating to method of wet-granulation, but discloses amethod for re-sizing granulation by re-binding microscopic particles ofpolyethylenoxide which is broken up by spraying water, which becomeshighly thread-like in appearance.

The “sizing” in the present Specification is different from the unitoperation of “granulation” that is normally conducted by persons in thisfield, and it is also different from the process whereby a portion of aspecific size is extracted by a sifting operation, and the like.

The “granulation” in the present Specification means a series of unitoperations by which a granulated product of good uniformity ismanufactured by binding particles to one another in order to improveadhesion and scattering of fine powder. In particular, when apharmaceutical preparation with a low drug dose and good uniformity ofcontent is to be manufactured, the drug is separately pulverized byitself, or pulverized after mixing with some of the additives to makefine particles in order to guarantee uniformity of content. Then agranulation process is generally conducted using a fluidized bedgranulator. Consequently, growth of the particles is promoted by“granulation” and therefore, a powder with a large particle diameter andlarge specific volume is manufactured.

In contrast to this, “sizing” is a series of unit procedures wherebywater is sprayed onto the polyethylene oxide (Also PEO hereafter) powderwith a high viscosity (commercial product) that is used in the presentinvention to manufacture powder particles (sized product) having apre-determined particle diameter and a pre-determined specific volume.In detail, “polyethylene oxide sized products (Also PEO sized productshereafter)”, for instance, in contrast to the case that part or all ofparticle breaks down into very fine particle when water is sprayed ontoa PEO powder (commercial products) used in the present invention andbecome powder products being bound irregularly after drying, the caseusing the polyethylene oxide sizing agent used in the present invention,the PEO powder is sized to the powder particle which shows specificrange of particle size and specific range of specific volume as a resultof keeping the PEO powder from breaking down into very fine particlesand/or as a result of re-binding into spherical shape during drying, andthe like, are contained. That is, the “sizing” in the presentspecification means a series of single operations, not by which the PEOparticles grow, but by which very fine particles of PEO that have beenbroken down by spraying with water re-bind during drying and re-form apowder of a size and specific volume appropriate for tableting.

The “particle diameter” in the present specification is represented bythe average particle diameter defined as the cumulative 50% averageparticle diameter of the powder (μm) and the amount of fine powder (%)of 75 μm or smaller. Specific volume is represented by the volume perunit weight of the powder (ml/g).

“Comprises essentially no organic solvent” or “uses essentially noorganic solvent” in the present specification means in addition to thefact that water only is always used as the solvent, organic solventremains and/or is used within a range that is pharmaceuticallyacceptable, or organic solvent remains and/or is used within the rangeof environmental standards. To this extent, it does not excludecompositions that comprise organic solvent within a range that ispharmaceutically acceptable or within a range that does not exceedenvironmental standards.

The controlled-release pharmaceutical composition or the sized productof the present invention will now be described in detail:

There are no particular restrictions to the drug used in the presentinvention as long as it is an active ingredient that is effective interms of treatment or in terms of prevention. Examples of this drug areanti-inflammatory, antipyretics, anticonvulsants, or analgesics such asindomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen,phenylbutazone, oxyphenbutazone, mepyrizole, aspirin, etenzamide,acetaminophen, aminopyrine, phenacetin, butyl bromide scopolamine,morphine, ethomidrin, pentazocin, fenoprofen calcium, naproxen,celecoxib, valdecoxib, and tramadol, anti-rheumatic drugs such asetodolac, anti-tuberculosis drugs such as isoniazide, and ethambutolhydrochloride, drugs for treatment of circulatory disorders such asisosorbide nitrate, nitroglycerin, nifedipine, barnidepinehydrochloride, nicardipine hydrochloride, dipyridamol, amrinone,indenolol hydrochloride, hydralazine hydrochloride, methyl dopa,furosemide, spironolactone, guanetidine nitrate, reserpine, amothrololhydrochloride, lisinopril, methoprolol, pyrocarbine, and talsaltan,neuroleptics such as chloropromazine hydrochloride, amitripitylinehydrochloride, nemonapride, haloperidol, moperon hydrochloride,perfenazine, diazepam, lorazepam, chlordiazepoxide, azinazolam,alprazolam, methylphenidate, milnasipran, peroxetin, risperidone, andsodium valproate, antiemetics such as metoclopramide, ramosetronhydrochloride, granisetron hydrochloride, ondansetron hydrochloride, andazasetron hydrochloride, antihistamines such as chlorpheniramine maleateand diphenhydramine hydrochloride, vitamins such as thiamine nitrate,tocopherol acetate, cycothiamine, pyridoxal phosphate, cobamamide,ascorbic acid, and nicotinamide, drugs for gout such as allopurinol,colchicine, and probenecid, drugs for Parkinson's disease such aslevodopa and selegiline, hypnotic sedatives such as amobarbitol,bromovaleryl urea, midazolam, and chloral hydrate, anti-malignant tumordrugs such as fluorouracil, carmofur, acralvidine hydrochloride,cyclophosphamide, and thiodepa, anti-allergy drugs such aspseudoephedrin and terfenadine, drugs used to treat decongestant such asphenylpropanolamine and ephedrines, drugs used for diabetes such asacetohexamide, insulin, torbutamide, desmopressin, and glypizine,diuretics such as hydrochlorothiazide, polythiazide, and triamuteren,bronchodilators such as aminophylline, formoterol furmate, andtheophylline, antitussives such as codeine phosphate, noscapine,dimemorphan phosphate, and dextromethorphan, anti-arrhythmia drugs suchas quinidine nitrate, digitoxin, propaphenone hydrochloride, andprocainamide, topical anesthetics such as ethyl aminobenzoate,lidocaine, and dibucaine hydrochloride, anti-epilepsy drugs such asphenyloin, ethosuximide, and primidone, synthetic corticosteroids suchas hydrocortisone, prednisolone, triamcinolone, and betamethazone, drugsfor the digestive tract such as famotidine, ranitidine hydrochloride,cimetidine, sucralfate, sulpiride, tepreson, pravatol, 5-aminosalicylicacid, sulfathalazin, omeprazol, and lansoprazole, drugs for the centralnervous system such as indeloxazine, idepenon, thiaprid hydrochloride,biphemelan hydrochloride, and calcium homopantothenate, drugs fortreatment of hyperlipidemia such as pravastatin sodium, simvastatin,lovastatin, and atorvastatin, antibiotics such as ampicillinhydrochloride phthalidyl, cefotetan, and josamycin, BPH drugs such astamsulosin, doxazosin mesylate, and terazosin hydrochloride, anti-asthmadrugs such as pranlukast, zafirlukast, albuterol, ambroxol, budesonide,and reperbutenol, drugs used to improve peripheral circulation ofprostaglandin I derivatives such as beraprost sodium, anticoagulants,hypotensive drugs, drugs used to treat heart failure, drugs used totreat the various complications of diabetes, drugs used to treat gastriculcers, drugs used to treat skin ulcers, drugs used to treathyperlipidemia, anti-asthma drugs, and the like. The drug can be used infree form or as a salt that is pharmaceutically acceptable. Moreover,one or a combination of two or more drugs can be used. Furthermore, evenbetter results are obtained from the present invention when a very smallamount of active ingredient that is effective in terms of treatment orprevention or a drug that is effective in low doses and is slightlywater soluble is used as the drug in the present invention. Of theabove-mentioned drugs, tamsulosin is particularly preferred as the drug.

The chemical name for tamsulosin is(R)(−)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamideand it is represented by the following structural formula. It was firstdisclosed together with its pharmaceutically acceptable salts inJapanese Kokai Patent No. Sho 56 (1981)-110665.

It is known that tamsulosin and its salts have adrenalin α_(1A)receptor-blocking activity, in other words, the same hydrochloride(tamsulosin hydrochloride) has the ability to block the α₁ receptor ofthe urethra and prostate and therefore is a popular drug for reducingpressure applied to the prostate along the pressure curvature inside theurethra and for improvement of the dysuria that accompaniesprostatomegaly. Tamsulosin hydrochloride is also a drug that isclinically very useful in that it has been recognized as clinicallyeffective for the treatment of lower urinary tract disorders.

Tamsulosin and its pharmaceutically acceptable salts can be easilyprocured by the manufacturing method entered in Japanese Kokai PatentsNo. Sho 56-110665 and No. Sho 62-114952, or by manufacturing inaccordance with this method.

Tamsulosin can form a pharmaceutically acceptable acid or a baseaddition salt with a wide variety of inorganic and organic salts andbases. Such salts are also a part of the present invention. Examples aresalts of inorganic acids, such as hydrochloric acid, sulfuric acid, andphosphoric acid, salts of organic acids, such as fumaric acid, malicacid, citric acid, and succinic acid, salts of alkali metals, such assodium and potassium, and salts of alkali earth metals, such as calciumand magnesium. Hydrochlorides are most preferred in the presentinvention and these salts can be manufactured by conventional methods.

The amount of drug that is added is usually selected as needed and usedas needed based on the type of drug and medical use (indications), andthere are no special restrictions as long as it is the amount that iseffective in terms of treatment or prevention. A drug that is effectivein very small doses (low-dose drug) is particularly preferred becausethe desired effects of the present invention are even better. However,it can be easily assumed that uniformity of content can even beaccomplished with drugs that are effective in high doses (high-dosedrugs), and therefore, there are no particular restrictions to theamount of drug that is added. This amount that is added is illustratedlater using a hydrogel sustained-release pharmaceutical preparation.However, it is preferably 85 wt % or less, more preferably 80 wt % orless, further preferably 50 wt %, and more further preferably 10 wt % orless, of the total pharmaceutical preparation. It is 1 wt % or less whenthe drug is tamsulosin. The dose of tamsulosin or its pharmaceuticallyacceptable salt is determined as needed in accordance with theindividual case taking into consideration the route of administration,the symptoms of the illness, the age and sex of the administrationsubject, and the like. The dose of tamsulosin hydrochloride is normallyapproximately 0.1 mg to 1.6 mg/day of active ingredient to one adult byoral administration and this is administered orally once a day.

There are no special restrictions to the polyethylene oxide (Also PEOhereafter) that is used in the present invention as long as it is onewith which release of drug from the controlled-release pharmaceuticalpreparation containing PEO as the sustained release base can becontrolled. Examples of this PEO are POLYOX® WSR-303 (viscosity-averagemolecular weight of 7,000,000, viscosity of 7,500 to 10,000 mPa·s(millipascal second: in an aqueous 1% W/V solution at 25° C.), POLYOX®WSR Coagulant (viscosity-average molecular weight of 5,000,000,viscosity of 5,500 to 7,500 mPa·s (in an aqueous 1% W/V solution at 25°C.)), POLYOX® WSR-301 (viscosity-average molecular weight of 4,000,000,viscosity of 1,650 to 5,500 mPa·s (in an aqueous 1% W/V solution at 25°C.)), and POLYOX® WSR N-60K (viscosity-average molecular weight of2,000,000, viscosity of 2,000 to 4,000 mPa·s (in an aqueous 2% W/Vsolution at 25° C.) (all manufactured by The Dow Chemical Company),ALKOX® E-75 (viscosity-average molecular weight of 2,000,000 to2,500,000, viscosity of 40 to 70 mPa·s (in an aqueous 0.5% W/V solutionat 25° C.)), ALKOX® E-100 (viscosity-average molecular weight of2,500,000 to 3,000,000, viscosity of 90 to 110 mPa·s (in an aqueous 0.5%W/V solution at 25° C.)), ALKOX® E-130 (viscosity-average molecularweight of 3,000,000 to 3,500,000, viscosity of 130 to 140 mPa·s (in anaqueous 0.5% W/V solution at 25° C.)), ALKOX® E-160 (viscosity-averagemolecular weight of 3,600,000 to 4,000,000, viscosity of 150 to 160mPa·s (in an aqueous 0.5% W/V solution at 25° C.)), and ALKOX® E-240(viscosity-average molecular weight of 4,000,000 to 5,000,000, viscosityof 200 to 240 mPa·s (in an aqueous 0.5% W/V solution at 25° C.) (allmanufactured by Meisei Chemical Works, Ltd.), and PEO-8(viscosity-average molecular weight of 1,700,000 to 2,200,000, viscosityof 20 to 70 mPa·s (in an aqueous 0.5% W/V solution at 25° C.)), PEO-15viscosity-average molecular weight of 3,300,000 to 3,800,000, viscosityof 130 to 250 mPa·s (in an aqueous 0.5% W/V solution at 25° C.)), andPEO-18 (viscosity-average molecular weight of 4,300,000 to 4,800,000,viscosity of 250 to 480 mPa·s (in an aqueous 0.5% W/V solution at 25°C.)) (all manufactured by Sumitomo Seika Chemicals Co., Ltd.). Of these,PEO with a high viscosity at the time of gelling or with a highviscosity-average molecular weight is preferred. PEO with a viscosity of2,000 mPa·s or higher in an aqueous 2% solution (25° C.) or with aviscosity-average molecular weight of 2,000,000 to 10,000,000 ispreferred. PEO with a viscosity-average molecular weight of 4,000,000 to10,000,000 is further preferred and that with a viscosity-averagemolecular weight of 5,000,000 to 10,000,000 is more further preferred.PEO with a viscosity-average molecular weight of 7,000,000 (forinstance, POLYOX® WSR-303) is optimal. One or a combination of two ormore PEO of different molecular weights, grades, and the like can beused.

There are no special restrictions to the amount of polyethylene oxideadded as long as it is the amount with which release of the drug fromthe hydrogel-forming sustained-release pharmaceutical preparation canusually be controlled. However, it is preferred that it be 10 to 95 wt %per the total pharmaceutical preparation, and 15 to 90 wt % per thetotal pharmaceutical preparation is further preferred. Moreover, theamount of PEO that is added is preferably 70 mg or more, furtherpreferably 100 mg or more, more further preferably 150 mg or more, per 1unit of the pharmaceutical preparation. If the drug is tamsulosinhydrochloride, the amount of PEO added is preferably 100 mg to 300 mg,further preferably 150 mg to 250 mg, more further preferably 200 mg. Acontrolled-release pharmaceutical preparation (tablet) that ismanufactured using this amount of PEO with a viscosity-average molecularweight of 7,000,000 (for instance, PEO with the brand name POLYOXWSR-303) from among the above-mentioned types of PEO will provide markedeffects as a controlled-release pharmaceutical preparation.

There are no special restrictions to the size controlling agent forpolyethylene oxide that is used in the present invention as long as itis powder particles that are suitable for tableting PEO of a highviscosity with an aqueous system. This size controlling agent is asubstance having the appropriate plasticity and binding ability. Solidpolyethylene glycol (PEG hereafter), low viscosity grades ofhydroxypropylmethyl cellulose (HPMC hereafter), hydroxypropyl cellulose(HPC hereafter), and methyl cellulose (MC hereafter), and the like aregiven as this size controlling agent. This size controlling agent can beused dissolved and/or suspended in water. Moreover, because theabove-mentioned effects can be realized with PEG by dissolving part ofthe PEG in solid form with high water solubility using sprayed water, itcan be used as the PEO size controlling agent of the present invention,even if it is added in solid form.

PEG that is solid at ordinary temperature (PEG4000, PEG6000, PEG8000) ispreferred as the PEG. Macrogol 4000 (Japanese Pharmacopoiea, molecularweight of 2,600 to 3,800, brand name: Macrogol 4000/Sanyo ChemicalIndustries, Ltd., NOF Corporation, Lion Corporation, and the like),Macrogol 6000 (Japan Pharmaceopoiea, molecular weight of 7,300 to 9,300,brand name: Macrogol 6000/Sanyo Chemical Industries, Ltd., NOFCorporation, Lion Corporation, and the like), Macrogol 20000 (JapanPharmacopoeia, molecular weight of 15,000 to 25,000, brand name:Macrogol 20000 (Sanyo Chemical Industries, Ltd., NOF Corporation, LionCorporation, and the like), polyethylene glycol 8000 (USP/NF, molecularweight of 7,000 to 9,000, brand name: Polyethylene glycol 8000/The DowChemical Company, and the like), and the like are specifically given.Low-viscosity grades of HPCM (viscosity of 2 to 15 mPa·s, aqueous 2% W/Vsolution, 20° C.) are preferred. The brand names of TC-5E (viscosity of3 mPa·s, aqueous 2% W/V solution, 20° C., Shin-Etsu Chemical Co., Ltd.),TC-5R (viscosity of 6 mPa·s, aqueous 2% W/V solution, 20° C., Shin-EtsuChemical Co., Ltd.), TC-5S (viscosity of 15 mPa·s, aqueous 2% W/Vsolution, 20° C., Shin-Etsu Chemical Co., Ltd.), Methocel E3 (viscosityof 3 mPa·s, aqueous 2% W/V solution, 20° C., The Dow Chemical Company),Methocel E5 (viscosity of 5 mPa·s, aqueous 2% W/V solution, 20° C., TheDow Chemical Company), Methocel E15 (viscosity of 15 mPa·s, aqueous 2%W/V solution, 20° C., The Dow Chemical Company), and the like arespecifically given. Low viscosity grades (viscosity of 2 to 10 mPa·s,aqueous 2% W/V solution, 20° C.) are preferred as the HPC. The brandnames of HPC-SSL (viscosity of 3.0 to 5.9 mPa·s, aqueous 2% W/Vsolution, 20° C., Nippon Soda Co., Ltd.), HPC-SL (viscosity of 2.0 to2.9 mPa·s, aqueous 2% W/V solution, 20° C., Nippon Soda Co., Ltd.),HPC-L (viscosity of 6.0 to 10.0 mPa·s, aqueous 2% W/V solution, 20° C.,Nippon Soda Co., Ltd.), and the like are specifically given. Lowviscosity grades (viscosity of 2 to 15 mPa·s, aqueous 2% W/V solution,20° C.) are preferred as the MC. The brand name of Methocel A115-LV(viscosity of 15 mPa·s, aqueous 2% W/V solution, 20° C., The DowChemical Company), Metolose SM4 (viscosity of 4 mPa·s, aqueous 2% W/Vsolution, 20° C., Shin-Etsu Chemical Co., Ltd.), Metolose SM15(viscosity of 15 mPa·s, aqueous 2% W/V soluition, 20° C., Shin-EtsuChemical Co., Ltd.), and the like are specifically given.

PEG and/or HPMC are further preferred as the size controlling agent forpolyethylene oxide, and PEG is the ideal size controlling agent of thepresent invention, even if added in powder form. One or a combination oftwo or more size controlling agents of the present invention can beused. The method whereby water or an aqueous solution containing abinder is sprayed after physical mixing, the method whereby an aqueoussolution containing a size controlling agent is sprayed, and the likeare given as the state in which the size controlling agent is used.

There are no special restrictions to the amount of size controllingagent for polyethylene oxide that is used as long as it is the amountthat can size PEO with an aqueous system. It is usually 0.5 to 60 wt %per unit of pharmaceutical preparation.

When PEG as the size controlling agent of the present invention issprayed in the form of an aqueous solution, the amount is preferably 0.5to 3 wt %, further preferably 1 to 2 wt %, per unit of pharmaceuticalpreparation. When a substance other than PEG as the size controllingagent of the present invention is sprayed in the form of an aqueoussolution, the amount is preferably 0.5 to 3 wt %, further preferably 1to 2 wt %, per unit of pharmaceutical preparation. Moreover, when PEG isused as a solid size controlling agent, the amount is preferably 5 to 60wt %, further preferably 10 to 30 wt %.

The amount of substance other than PEG as the size controlling agentthat is used in the form of an aqueous solution is small when comparedto the amount that is usually used as a binder (3 to 5 wt %). If lessthan 0.5 wt % is used, there will be problems in that the desired sizingwill not be performed and there will be a large amount of fine powder,there will be a reduction in uniformity of drug content, a powder ofpoor fluidity will further be produced, and the like. If the amount ismore than 3 wt %, granulation will proceed to too great an extent and asa result, fluidity of the powder will decrease, the powder will be toolarge, re-pulverizing after drying will be necessary, and the like andas a result, there is concern that problems will remain with uniformityof drug content.

There are no special restrictions to the controlled-releasepharmaceutical composition of the present invention as long as it is apharmaceutical composition, particularly a pharmaceutical preparation,with which release of the drug is controlled. The hydrogelsustained-release pharmaceutical preparation in InternationalPublication Pamphlet No. 94/06414 is an example of thiscontrolled-release pharmaceutical composition (particularly acontrolled-release pharmaceutical preparation). The above-mentionedhydrogel sustained-release pharmaceutical preparation consists of adrug, a gelation enhancer with a specific solubility (hydrophilic base),and PEO of a specific molecular weight as the basic structuralcomponents. Moreover, when PEO is used as the controlled-releasepharmaceutical preparation, yellow ferric oxide and/or red ferric oxideare added as PEO stabilizers, as entered in International PublicationPamphlet No. 01/10466. The mechanism of drug release is as entered inInternational Publication Pamphlet No. 94/06414 with any pharmaceuticalpreparation. That is, the controlled-release pharmaceutical preparationabsorbs water during its stay in the upper digestive tract to undergosubstantially complete gelation (70% or higher, preferably 80% orhigher) and then it moves to the lower digestive tract as the surface ofthe pharmaceutical preparation is eroded and drug continues to bereleased with erosion. Therefore, good and continuous release andabsorption of the drug are performed, even in the colon with a smallwater content. The controlled-release pharmaceutical composition orhydrogel sustained-release pharmaceutical preparation can also containpharmaceutical fillers as needed.

When the controlled-release pharmaceutical preparation of the presentinvention further contains a hydrophilic base, there are no specialrestrictions to the hydrophilic base (gelation enhancer) required in thepresent invention as long as it can be dissolved before the PEO that isrequired in the present invention gels. The amount of water needed todissolve 1 g of this hydrophilic base is preferably 5 ml or less (20±5°C.), further preferably 4 ml or less (same temperature). Hydrophilicpolymers such as polyethylene glycol (for instance, Macrogol 400,Macrogol 1500, Macrogol 4000, Macrogol 6000, and Macrogol 20000 (allmanufactured by NOF Corporation)) and polyvinyl pyrrolidone (forinstance, PVP® K30 (BASF)), sugar alcohols such as D-sorbitol andxylitol, saccharides such as sucrose, maltose, lactulose, D-fructose,dextran (for instance, Dextran 40), and glucose, surfactants such aspolyoxyethylene-hydrogenated castor oil (for instance, Cremophor® RH40(BASF), HCO-40, HCO-60 (Nikko Chemicals), polyoxyethylenepolyoxypropylene glycol (for instance, Pluronic® F68 (Asahi Denka Co.,Ltd.) and polyoxyethylene sorbitan higher fatty acid esters (forinstance, Tween 80 (Kanto Kagaku Co., Ltd.), salts such as sodiumchloride and magnesium chloride, organic acids such as citric acid andtartaric acid, amino acids such as glycine, β-alanine, and lysinehydrochloride, and aminosaccharides such as meglumine are given asexamples of the hydrophilic base. Polyethylene glycol, sucrose, andpolyvinyl pyrrolidone are preferred and polyethylene glycol(particularly Macrogol 6000 and Macrogol 8000) are further preferred.One or a combination of two or more hydrophilic bases can be used in thepresent invention.

The amount of hydrophilic base (gelation enhancer) that is used ispreferably 5 to 80 wt % per total pharmaceutical preparation, furtherpreferably 5 to 60 wt % per total pharmaceutical preparation.Furthermore, when the gelation enhancer serves as what is called a sizecontrolling agent in the present invention, the amount of gelationenhancer is calculated as the combined amount.

It is preferred that yellow ferric oxide and/or red ferric oxide isadded as the PEO stabilizer to the controlled-release pharmaceuticalpreparation of the present invention (U.S. Ser. No. 9,629,405 (refer tocorresponding International Patent Publication Pamphlet No. 01/10466)).The amount of this stabilizer is preferably 1 to 20 wt %, furtherpreferably 3 to 15 wt %, per total mount of pharmaceutical preparationwhen it is a physical mixture in a matrix. For instance, the amount ofred ferric oxide is preferably 5 to 20 wt %, further preferably 10 to 15wt %, per total amount of pharmaceutical preparation. The amount ofyellow ferric oxide is preferably 1 to 20 wt %, further preferably 3 to10 wt %. When added with a film coating, the amount is preferably 0.3 to2%, further preferably 0.5 to 1.5%, per tablet weight. The concentrationof yellow ferric oxide or red ferric oxide that is present in the filmin this case is preferably 5 to 50%, further preferably 10 to 20%. The“physical mixture in a matrix” used here is defined as a means withwhich, for instance, drug, polyethylene oxide and the above-mentionedferric oxide are uniformly dispersed so that the drug and theabove-mentioned ferric oxide are uniformly dispersed in the PEO thatbecomes the main base of the controlled-release pharmaceuticalpreparation. Moreover, the “film coating” here is defined as forinstance, dissolution or suspension of the above-mentioned ferric oxidein a water-soluble polymer solution such as hydroxypropyl methylcellulose and coating tablets that have been separately prepared withthis in the form of a thin film. The yellow ferric oxide and/or redferric oxide of the present invention can usually be found anywhere inthe pharmaceutical preparation. For instance, the yellow ferric oxideand/or red ferric oxide can be present in the film of film coating, inthe granulation product of granulation, or in the matrix (for instance,near the polyethylene oxide).

A variety of pharmaceutical fillers are further used as needed with thecontrolled-release pharmaceutical composition of the present inventionto make a pharmaceutical preparation. There are no special restrictionsto these drug fillers as long as they are pharmaceutically andpharmacologically acceptable. For instance, binders, disintegratingagents, sour flavorings, foaming agents, artificial sweeteners,fragrances, lubricants, coloring agents, stabilizers, buffer agents, andantioxidants are used. Hydroxypropylmethyl cellulose, hydroxypropylcellulose, polyvinyl alcohol, methyl cellulose, hydroxypropyl cellulose,polyvinyl alcohol, methyl cellulose, and gum arabic are examples ofbinders. Corn starch, starches, carmellose calcium, carmellose sodium,and hydroxypropyl cellulose with a low degree of substitution areexamples of the disintegrating agent. Citric acid, tartaric acid, andmalic acid are examples of the sour flavoring. Sodium bicarbonate is anexample of the foaming agent. Saccharin sodium, dispotassiumglycyrrhizinate, aspartame, stevia, and somatin are examples ofartificial sweeteners. Lemon, lemon lime, orange, and menthol areexamples of fragrances. Magnesium stearate, calcium stearate, sucrosefatty acid ester, polyethylene glycol, talc, and stearic acid areexamples of lubricants. Yellow ferric oxide, red ferric oxide, yellowfood colorings No. 4 and No. 5, red food colorings No. 3 and No. 102,and blue food coloring No. 3 are examples of coloring agents. It isconfirmed that yellow ferric oxide and red ferric oxide have aparticularly marked photostabilizing effect on tamsulosin hydrochloridewhen used in controlled-release pharmaceutical preparations to whichtamsulosin hydrochloride have been added, and these coloring agents arealso given as photostabilizers. The amount of coloring agent is usuallya trace (a trace to 0.1 wt %). However, when added as the stabilizer,there are no special restrictions to the amount as long as it usuallyprovides stabilizing effects as a photostabilizer, but it is normally0.1 to 2 wt %, preferably 0.5 to 1 wt %. Citric acid, succinic acid,fumaric acid, tartaric acid, ascorbic acid and their salts, glutamicacid, glutamine, glycine, aspartic acid, alanine, arginine, and theirsalts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoricacid, boric acid and their salts, and the like are given as bufferagents. Ascorbic acid, dibutyl hydroxytolueme and propyl gallate aregiven as examples of antioxidants. Appropriate amounts of one or acombinate of two or more pharmaceutical fillers can be added as needed

The method of manufacturing the controlled-release pharmaceuticalcomposition or the sized product of the present invention will now bedescribed in detail:

The processes involved in the manufacture of the controlled-releasepharmaceutical composition of the present invention are essentially asfollow:

(1) Process of pulverization and mixing of components,

(2) Process of suspending and/or dissolving PEO size controlling agent(process of preparation of size controlling agent solution)

(3) Process of sizing and drying whereby the size controlling agentsolution that was prepared in above-mentioned process (2) is sprayedonto PEO of a high viscosity with a molecular weight of 2,000,000 orhigher (process of preparing PEO sizing product (powder particles)

(4) Process of uniformly mixing PEO sizing product obtained byabove-mentioned process (3) and a pharmaceutically acceptable filler

(5) Process of molding

(1) Process of Pulverization and Mixing of Components

There are no special restrictions to the equipment and means of thisprocess as long as it is a method whereby usually pulverization ispharmaceutically possible. There are no special restrictions to theequipment or means of the process of mixing of each component thatfollows pulverization as long as it is a method by which usually eachcomponent can be uniformly mixed pharmaceutically.

A hammer mill, ball mill, jet pulverization device, and colloid mill areexamples of the pulverization device. There are no special restrictionsto the pulverization conditions as long as they are selected as needed.For instance, in the case of the hammer mill, punch diameter of thescreen is usually 0.5 to 5 mm, preferably 0.8 to 2 mm. The powder feedspeed is usually 50 to 500 g/minute, preferably 100 to 200 g/minute. AV-type mixer, ribbon mixer, container mixer, and high-shear agitatingmixer are examples of the mixing device. There are no specialrestrictions to the mixing conditions as long as they are selected asneeded. For instance, in the case of a container mixer with a capacityof 20 L, the rotating speed is usually 10 to 40 rpm, preferably 20 to 30rpm. It is preferred that each component is pre-mixed using a sieve of,for instance, 42 mesh (opening of 355 μm) for pulverizationpre-treatment of each component.

(2) Process of Suspending and/or Dissolving the PEO Size ControllingAgent (Process of Preparation of Size Controlling Agent Solution)

There are no particular restrictions to the equipment or means of thisprocess as long as it is a method whereby the size controlling agent canbe uniformly dissolved and/or suspended.

The magnetic stirrer and propeller mixer are examples of the suspending(dissolving) device. There are no special restrictions to the conditionsfor preparing the size controlling agent solution as long as they areselected as needed. There are no special restrictions to theconcentration of the size controlling agent solution as long as it isthe concentration of size controlling agent that is sprayed by fluidizedbed granulation. This concentration is usually 1 to 50% W/W, preferably2 to 30% W/W. With PEG it is 1 to 50% W/W, preferably 5 to 30% W/W. WithHPMC, it is 1 to 20% W/W, preferably 2 to 10% W/W. With HPC it is 1 to20% W/W, preferably 2 to 10% W/W. With MC it is 1 to 20% W/W, preferably2 to 10% W/W.

(3) Process of Sizing and Drying Whereby the Size Controlling AgentSolution that was Prepared in Above-Mentioned Process (2) is Sprayedonto PEO of a High Viscosity with a Molecular Weight of 2,000,000 orHigher (Process of Preparing PEO Sized Product (Powder Particles)

There are no special restrictions to the equipment or means of thisprocess as long as it is a method by which PEO with a high viscosity canbe wet sized using an aqueous solution of a PEO size controlling agent.

Examples of the spraying device (method) are the high-shear agitationgranulation method, crushing (pulverization) granulation method,fluidized bed granulation method, extrusion granulation method, tumblinggranulation method, and spray granulation method, or device for by usingits method thereof. The fluidized bed granulation method or device ispreferred and the tumbling fluidized bed granulation or device isparticularly preferred because it is possible to easily and uniformlymix a low-dose drug and hydrophilic base with PEO of a high viscosity.

Examples of the sizing device are the fluidized bed granulator (forinstance, the flow coater, Freund Industry Co., Ltd., the GPCG, GlattCo., Ltd.), a granulation and coating device equipped with a horizontalrotating disc having a flat powder contact part (for instance, acentrifugal fluidization and granulator (for instance, the CF granulatorof Freund Industry Co., Ltd.), and a granulation and coating devicehaving an aeration part and wherein a rotating disk with a flat surfaceis placed at the bottom of the fluidized bed (for instance, the spiralflow or flow coater with rotor container, both made by Freund IndustryCo., Ltd.).

There are no special restrictions to the amount of water during sizingas long as it is the amount with which size controlling agent (andpreferably drug) can be uniformly dissolved and/or suspended(dispersed). When PEG is used in solid form, there are no specialrestrictions as long as it is the amount that can size the PEO.

When used in liquid form, it is usually 10 wt % or less, preferably 8 wt% or less, further preferably 5 wt % or less, per PEO. There are nospecial restrictions to the method of adding water during sizing as longas it is a method by which a nonuniform product consisting of mass ofpowder aggregate and untreated powder is not usually produced. Examplesare the continuous spraying method whereby water is continuously addedand the intermittent spraying method whereby a drying process andfurther, a shaking process are set up somewhere in the granulationprocess.

There are no special restrictions to the speed with which water is addedduring granulation as long as it is a speed with which a nonuniformproduct consisting of masses of powder aggregate and untreated powder isnot usually produced. For instance, it is usually 0.1 to 1 wt %/min,preferably 0.2 to 0.8 wt %/min, further preferably 0.4 to 0.6 wt %/min,per PEO in the case of fluidized bed granulation.

There are no special restrictions to the temperature of the powderduring sizing as long as it is a temperature that will not inducethermal denaturation of the PEO. For instance, it is 20° C. to themelting point of PEO (62 to 67° C.), preferably 20° C. to 50° C.,further preferably 20° C. to 35° C., ideally 25° C. to 30° C.

There are no special restrictions to the equipment and means of thedrying process as long as it is a method whereby the sized product isdried. Examples of the drying device are the fluidized bed granulator(for instance, the flow coater, Freund Industry Co., Ltd., the GPCG,Glatt Co., Ltd.), a granulation and coating device equipped with ahorizontal rotating disc having a flat powder contact part (forinstance, a centrifugal fluidization and granulator (for instance, theCF granulator of Freund Industry Co., Ltd.), and a granulation andcoating device having an aeration part and wherein a rotating disk witha flat surface is placed at the bottom of the fluidized bed (forinstance, the spiral flow or flow coater with rotor container, both madeby Freund Industry Co., Ltd.). There are no special restrictions to thedrying conditions as long as they are conditions under which a sizedarticle will usually dry in the fluidized bed. For instance, when dryinginlet temperature is set at 50° and drying is performed until the sizedarticle temperature becomes 40° C., drying of the sized article isalmost complete. The aeration drying method and reduced pressure dryingmethod can also be used as the drying method.

The powder particles (sized product) that are obtained can be evaluatedby the following methods:

[Average Particle Diameter]

The “average particle diameter” means the cumulative 50% averageparticle diameter. The average particle diameter can be determined withan automatic particle diameter distribution determination device (brandname: Robot Sifter, Seishin Enterprise Co., Ltd.), and the like. Usuallyit is approximately 50 to 500 μm, preferably approximately 60 to 300 μm,further preferably 80 to 200 μm.

[Amount of Very Fine Powder]

The “amount of very fine powder” means the amount of particles that are75 μm or smaller. Particle size can be determined with an automaticparticle diameter distribution determination device (brand name: RobotSifter, Seishin Enterprise Co., Ltd.), and the like. As an evaluationcriterion, the amount of particles that are 75 μm or smaller ispreferably 20% or less, further preferably 15% or less.

[Specific Volume]

Using a powder property determination device (Powder Tester PT-D,Hosokawa Micron Corporation), a specific amount of sample is placed on a20 mesh sieve and continuously allowed to fall naturally through afunnel into a receptacle with an inner capacity of 100 ml while beingvibrated. After the pile of sample is scraped off of the receptacle witha flat metal plate, the mass of the receptacle into which the sample hasbeen introduced is weighed and specific volume is calculated. It ispreferably 1.5 to 3.5 mL/g, further preferably 2.0 to 3.0 mL/g.

[Angle of Repose]

Using a powder property determination device (Powder Tester PT-D,Hosokawa Micron Corporation), the “angle of repose” is found by allowinga specific amount of sample to continuously fall onto a disc-shapeddetermination table as it is vibrated until the sample begins to spillfrom the edge of the table, forming a cone-shaped pile, and reading theangle of inclination of this pile with a protractor. As an evaluationcriterion, the angle of repose is preferably 450 or smaller, furtherpreferably 420 or smaller.

[Fluidity] (Degree of Compression)

Using a powder property determination device (Powder Tester PT-D,Hosokawa Micron Corporation), a specific amount of sample is placed on a20 mesh sieve and continuously allowed to fall naturally through afunnel into a receptacle with an inner capacity of 100 ml while beingvibrated. After the pile of sample is scraped off of the receptacle witha flat metal plate, the mass of the receptacle into which the sample hasbeen introduced is weighed and minimum apparent density is calculated. Atop vessel is further attached and excess powder is added and tappedwith a vibrator. The top vessel is removed and the pile of sample isscraped off of the receptacle with a flat metal plate. Then the mass ofthe receptacle into which the sample has been introduced is weighed andtapped apparent density is determined. The degree of compression of thepowder is calculated from the minimum density and the tapped densityusing the following formula. It is preferably 15% or less, furtherpreferably 10% or less.

Degree of compression (%)=(T−M)/T×100

T: Tapped density

M: Minimum density

(4) Process of Uniformly Mixing PEO Sizing Product Obtained byAbove-Mentioned Process (3) and a Pharmaceutically Acceptable Filler

There are no special restrictions to the equipment or means of thisprocess as long as it is a method whereby the PEO sized product obtainedby above-mentioned process (3) and pharmaceutically acceptable fillerare uniformly mixed. The method whereby they are uniformly mixed in oneor two processes selected from the group consisting of (1) the processof dissolving and/or suspending in the spraying liquid, (2) the processwhereby the powder particles are prepared, and (3) the process of beinguniformly mixed with a pharmaceutically acceptable filler is an example.

(5) Process of Molding

There are no special restrictions to the equipment or means of thisprocess as long as it is a method with which a pharmaceuticalcompression molded article (preferably tablets) is usually made.

Examples of the tableting device are rotary tablet machine (for instanceHT P-22, Hata Iron Works, Ltd.) and a single tablet machine (forinstance, KM-2, Okada Seiko Co., Ltd.). Examples of the tabletingconditions are 20 to 30 rpm as the number of rotations of the turn tableand a tableting pressure of 200 to 600 kgf/punch.

The sized product itself, or tablets, fine particles, granules, capsulesof sized product packed in, for instance, gelatin hard capsules, thatare made by conventional methods, and the like are given as thepharmaceutical composition (pharmaceutical preparation). There are nospecial restrictions to the method of manufacturing thecontrolled-release pharmaceutical composition of the present inventionor its pharmaceutical preparation as long as it is a method whereby thedesired pharmaceutical preparation is manufactured using combinations ofthe above-mentioned methods or conventional methods as needed.

PREFERRED EMBODIMENTS OF THE INVENTION

The present invention will now be explained in further detail withcomparative examples, examples, and experiments, but this does not meanthat the present invention is limited to these examples and experiments.

Furthermore, although the examples of the present invention include anexample in which the composition does not comprise a drug, this exampleis one where a very small dose of drug is used in the pharmaceuticalpreparation of the present invention, that is, a trace of drug (a tracedose that is effective in terms of treating or preventing disease) thatis so small that it will not affect the properties of the PEO sizedproduct is used in the pharmaceutical preparation of the presentinvention.

Example 1

Four parts of Macrogol 6000 were dissolved in 36 parts of water whilebeing mixed with a magnetic stirrer to prepare the spraying liquid(concentration of 10% W/V). Next, 400 parts PEO (POLYOX® WSR-303, TheDow Chemical Company) were introduced to a fluid bed granulator (FlowCoater, Freund Industry Co., Ltd.) and sized by spraying theabove-mentioned spraying liquid with an inlet temperature of 30° C.,spraying speed of 5 g/minute, and spraying/drying/shaking cycle of 20seconds/30 seconds/10 seconds. After granulation, the sized product wasdried for 30 minutes at an inlet temperature of 40° C. to obtain thesized product of the present invention.

Example 2

The sized product of the present invention was obtained by the method inExample 1 using 2 parts of Macrogol 60000 and 38 parts of water.

Example 3

The sized product of the present invention was obtained by the samemanufacturing method as in Example 1 with the PEG being changed to HPMC(6 mPa·s) as the binder.

Reference 1 Comparative Examples 1 Through 4

The powder properties of commercial PEO (powder properties of unsizedproduct: Reference) will serve as Reference 1.

A comparative example sized product was obtained by the same method asin Example 1 using water (Comparative Example 1), PVP (ComparativeExample 2), sorbitol (Comparative Example 3), and Tween 80 (ComparativeExample 4) as the size controlling agent. The properties of the sizedproducts are shown in Table 1.

TABLE 1 Example Example Example Comparative Comparative ComparativeComparative Reference 1 2 3 Example 1 Example 2 Example 3 Example 4 1Size PEG PEG HPMC None PVP Sorbitol Tween80 Commercial controlling agent(water) unsized Weight ratio 1.0 0.5 1.0 None 1.0 1.0 1.0 product (%) toPEO Liquid 10 5 10 10 10 10 10 concentration (%) Average particle 136142 134 176 201 110 114 122 diameter (%) Amount of fine 13.3 11.2 14.62.8 0.2 37.7 26.6 21.0 powder (%) (<75 μm) Specific 2.72 2.92 2.75 3.423.19 2.42 2.26 2.27 volume (mL/g) Angle of 40 39 37 40 42 39 38 39repose (°) Degree of 8.0 12.5 10.6 20.2 15.2 7.0 10.5 11.4 compression(%)

<Results and Discussion>

The effects of each type of size controlling agent during aqueous sizingof PEO were studied.

When the commercial PEO product was observed with an electronmicroscope, the fine particles of about 10 μm had aggregated to formaggregated particles of 50 to 200 μm. When powder properties weredetermined, specific volume was 2.3 mL/g, there was approximately 21%fine powder of 75 μl or smaller, and the degree of compression, which isan indicator of fluidity, was 11.4%.

When the PEO was sized by being sprayed with water only without usingany size controlling agent whatsoever, granulation proceeded and theamount of fine powder of 75 μm or smaller decreased to approximately 3%.However, the product was bulky (specific volume of 3.4 ml/g) andfluidity was poor with the degree of compression being 20.2%. Electronmicrographs revealed particles that had bound together without beingbroken down into fine particles of uniform size (electron micrographswere not appended).

When PVP was used as the size controlling agent, the particles grew(granulation proceeded) more than when only water was used and as aresult, the amount of fine powder of 75 μm or smaller was approximately0%, specific volume was 3.2 ml/g, and fluidity was poor with the degreeof compression being 15.2%. A granulation product was observed inelectron micrographs wherein particles that had been broken down were ofa uniform size (electron micrographs were not appended).

The amount of fine powder of 75 μm or smaller increased to 38% and 27%with aqueous sorbitol and aqueous polysorbate solutions, respectively.Particles that had been broken down into fine particles were observed inthe electron micrographs (electron micrographs were not appended).

Fine powder of the appropriate size that contained 13% and 15% of finepowder of 75 μm or smaller was granulated using aqueous solutions of PEGand HPMC, respectively, without increasing the average particlediameter. Fluidity was also improved over that of the original PEOparticles with the degree of compression being 7.7% and 10.6%,respectively. A reduction in fine particles and the formation ofparticles with a smooth surface of 100 to 200 μm was observed inelectron micrographs (electron micrographs were not appended).

<Evaluations>

Granulation usually means a series of unit processes by which particlegrowth is promoted and decreases fine powder in order to eliminate theproblems of adhesion to the punch and scattering of powder duringtableting.

When sorbitol and polysorbate are used as the PEO size controllingagent, there is a large amount of fine powder and therefore, thesesubstances are not appropriate.

Sorbitol and polysorbate have a high plasticity and poor binding forceand therefore, when they are used as a PEO size controlling agent, it isthought that the PEO particles that have been broken down by sprayingwith an aqueous solution do not re-bind during drying and cannot besized.

When PVP is used as the PEO size controlling agent, there is a reductionin fine powder, but a powder of high specific volume and poor fluidityis produced and there are problems in terms of the above-mentionedtableting obstruction and weight uniformity. Therefore, PVP isundesirable.

PVP has poor plasticity and strong binding force and therefore, whenused as a PEO size controlling agent, it is thought the PEO particlesthat have been broken down into fine particles dry, and granulation tolarger particles proceeds.

When PEG or HPMC is used as the PEO size controlling agent, there is areduction in the amount of fine powder and a sized product of goodfluidity is obtained.

PEG and HPMC have the appropriate plasticity and binding force andtherefore, it appears that when they are used as a PEO size controllingagent, it is possible that fine PEO particles that have been broken downre-bind and dry in a state of good fluidity and with a smooth surface.

Example 4

First, 4.8 parts of Macrogol 6000 were mixed and dissolved in 14.4 partsof water using a magnetic stirrer. Then 0.8 part of tamsulosinhydrochloride that had been pre-pulverized with a hammer mill (SampleMill AP-S, using 1 mm screen, Hosokawa Micron Corporation) was suspended(partially dissolved) in this liquid while mixing with a magneticstirrer to prepare the spraying liquid. Next, 75.2 parts of Macrogol6000 and 400 parts of PEO (POLYOX® WSR-303, The Dow Chemical Company)were introduced to a fluidized bed granulator (FLOW COATER, FreundIndustry Co., Ltd.) and sizing was performed by spraying theabove-mentioned spraying liquid at an inlet temperature of 25° C.,spraying speed of 5 g/minute and spray/dry cycle of 20 seconds/40seconds. After sizing, the sized product was dried for 30 minutes at aninlet temperature of 40° C. to obtain the sized product of the presentinvention. The sized product had an average particle diameter of 94 μm,a specific volume of 2.27 mL/g, and angle of repose of 39°. Blendinguniformity of the drug in the sized product was good with drug contentbeing 97.3% at a standard deviation of 1.2%. After adding and mixing 2.4parts of magnesium stearate with 480.8 parts of this dry sized product,this mixture was made tableted at a tablet weight of 241.6 mg under atableting pressure of 400 kgf/punch from a 9 mm φ punch using a rotarytablet machine (HT P-22, Hata Iron Works, Ltd.) to obtain thecontrolled-release pharmaceutical preparation (tablets) of the presentinvention. The tablets that were obtained had few variations withstandard deviation of weight being 0.2%.

Example 5

First, 4.8 parts of Macrogol 6000 were mixed and dissolved in 14.2 partsof water using a magnetic stirrer. Then 1.0 part of tamsulosinhydrochloride that had been pre-pulverized with a hammer mill (SampleMill AP-S, using 1 mm screen, Hosokawa Micron Corporation) was suspended(partially dissolved) in this liquid while mixing with a magneticstirrer to prepare the spraying liquid. Next, 70.2 parts of Macrogol6000 and 375 parts of PEO (POLYOX® WSR-303, The Dow Chemical Company)were introduced to a fluidized bed granulator (FLOW COATER, FreundIndustry Co., Ltd.) and sizing was performed by spraying theabove-mentioned spraying liquid at an inlet temperature of 25° C.,spraying speed of 5 g/minute and spray/dry cycle of 20 seconds/40seconds. After sizing, the sized product was dried for 30 minutes at aninlet temperature of 40° C. to obtain the sized product of the presentinvention. The sized product had an average particle diameter of 93 μm,a specific volume of 2.22 mL/g, and angle of repose of 39°. Blendinguniformity of the drug in the sized product was good with drug contentbeing 97.7% at a standard deviation of 0.7%. After adding and mixing2.25 parts of magnesium stearate with 451 parts of this dry sizedproduct, this mixture was made tableted at a tablet weight of 181.3 mgunder a tableting pressure of 400 kgf/punch from a 7.5 mm φ punch usinga rotary tablet machine (HT P-22, Hata Iron Works, Ltd.) to obtain thecontrolled-release pharmaceutical preparation (tablets) of the presentinvention. The tablets that were obtained had few variations withstandard deviation of weight being 0.4%.

Example 6

First, 3.84 parts of Macrogol 6000 were mixed and dissolved in 9.76parts of water using a magnetic stirrer. Then 2.4 parts of tamsulosinhydrochloride that had been pre-pulverized with a hammer mill (SampleMill AP-S, using 1 mm screen, Hosokawa Micron Corporation) weresuspended in this liquid while mixing with a magnetic stirrer to preparethe spraying liquid. Next, 76.16 parts of Macrogol 6000 and 400 parts ofPEO (POLYOX® WSR-303, The Dow Chemical Company) were introduced to afluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.) andsizing was performed by spraying the above-mentioned spraying liquid atan inlet temperature of 25° C., spraying speed of 5 g/minute andspray/dry cycle of 20 seconds/40 seconds. After sizing, the sizedproduct was dried for 30 minutes at an inlet temperature of 40° C. toobtain the sized product of the present invention. The sized product hadan average particle diameter of 100 μm, a specific volume of 2.38 mL/g,and angle of repose of 38°. After adding and mixing 2.4 parts ofmagnesium stearate with 482.4 parts of this dry sized product, thismixture was made tableted at a tablet weight of 242.4 mg under atableting pressure of 400 kgf/punch from a 9 mm φ punch using a rotarytablet machine (HT P-22, Hata Iron Works, Ltd.) to obtain thecontrolled-release pharmaceutical preparation (tablets) of the presentinvention. The tablets that were obtained had few variations withstandard deviation of weight being 0.6%, and uniformity of content wasalso good at a standard deviation of 1.0%.

Example 7

First, 4.8 parts of Macrogol 6000 were mixed and dissolved in 14.4 partsof water using a magnetic stirrer. Then 0.8 part of tamsulosinhydrochloride that had been pre-pulverized with a hammer mill (SampleMill AP-S, using 1 mm screen, Hosokawa Micron Corporation) was suspendedin this liquid while mixing with a magnetic stirrer to prepare thespraying liquid. Next, 75.2 parts of Macrogol 6000 and 400 parts of PEO(POLYOX® WSR-303, The Dow Chemical Company) were introduced to afluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.) andsizing was performed by spraying the above-mentioned spraying liquid atan inlet temperature of 30° C., spraying speed of 5 g/minute andspray/dry cycle of 20 seconds/40 seconds. After sizing, the sizedproduct was dried for 30 minutes at an inlet temperature of 40° C. toobtain the sized product of the present invention. The sized product hadan average particle diameter of 106 μm, a specific volume of 2.33 mL/g,and angle of repose of 36°. After adding and mixing 2.4 parts ofmagnesium stearate with 480.8 parts of this dry sized product, thismixture was made tableted at a tablet weight of 241.6 mg under atableting pressure of 400 kgf/punch from a 9 mm φ punch using a rotarytablet machine (HT P-22, Hata Iron Works, Ltd.). The tablets that wereobtained had few variations with standard deviation of weight being0.5%. The tablets were further spray coated with a liquid in which 5.04parts of hydroxypropylmethyl cellulose (TC-5R, Shin-Etsu Chemical Co.,Ltd.), 0.95 part of Macrogol 6000, and 1.26 parts of yellow ferric oxidehad been dissolved/dispersed at an inlet temperature of 60° C., panrotating speed of 13 rpm, and coating liquid feed speed of 5 g/minuteusing an aeration-type coating device (Hi-Coater HCT-30, Freund IndustryCo., Ltd.) until the coating component was 3% of the tablet weight toobtain the controlled-release pharmaceutical preparation (film-coatedtablets) of the present invention. When the film-coated tablets thatwere obtained were observed microscopically, there was uniformdistribution of the coloring matter and the surface was smooth andgelation of the PEO was not seen.

Example 8

First, 1.2 parts of tamsulosin hydrochloride were dissolved in 148.8parts of water to prepare the spraying liquid. Next, 60 parts ofMacrogol 6000 and 300 parts of PEO (POLYOX®-WSR, The Dow ChemicalCompany) were introduced to a fluidized bed granulator (FLOW COATER,Freund Industry Co., Ltd.) and sizing was performed by spraying theabove-mentioned spraying liquid at an inlet temperature of 30° C.,spraying speed of 5 g/minute and spray/dry cycle of 20 seconds/40seconds. After sizing, the sized product was dried for 30 minutes at aninlet temperature of 40° C. to obtain the sized product of the presentinvention. The sized product had an average particle diameter of 108 μm,a specific volume of 2.66 mL/g, and angle of repose of 40°. After addingand mixing 1.8 parts of magnesium stearate with this dry sized product,this mixture was made tableted at a tablet weight of 121 mg under atableting pressure of 400 kgf/punch from a 7.0 mm φ punch using a rotarytablet machine (HT P-22, Hata Iron Works, Ltd.) to obtain thecontrolled-release pharmaceutical preparation (tablets) of the presentinvention. The tablets that were obtained had few variations withstandard deviation of weight being 0.6%. Moreover, the drug content ofthe tablets was 97.8% and uniformity of content was good at a standarddeviation of 1.4%.

Example 9

First, 2.0 parts of hydroxypropylmethyl cellulose (6 mPa·s) were mixedand dissolved in 18.0 parts of water using a magnetic stirrer. Then 0.8part of tamsulosin hydrochloride that had been pre-pulverized with ahammer mill (Sample Mill AP-S, using 1 mm screen, Hosokawa MicronCorporation) was suspended (partially dissolved) in this liquid whilemixing with a magnetic stirrer to prepare the spraying liquid. Next,78.0 parts of Macrogol 6000 and 400 parts of PEO (POLYOX® WSR-303, TheDow Chemical Company) were introduced to a fluidized bed granulator(FLOW COATER, Freund Industry Co., Ltd.) and sizing was performed byspraying the above-mentioned spraying liquid at an inlet temperature of30° C., spraying speed of 5 g/minute and spray/dry cycle of 20seconds/40 seconds. After sizing, the sized product was dried for 30minutes at an inlet temperature of 40° C. to obtain the sized product ofthe present invention. The sized product had an average particlediameter of 95 μm, a specific volume of 2.53 mL/g, and angle of reposeof 36°. Blending uniformity of the drug in the sized product was goodwith drug content being 101.6% at a standard deviation of 1.4%.

Example 10

First, 3.84 parts of Macrogol 6000 were mixed and dissolved in 10.56parts of water using a magnetic stirrer. Then 1.6 parts of tamsulosinhydrochloride that had been pre-pulverized with a hammer mill (SampleMill AP-S, using 1 mm screen, Hosokawa Micron Corporation) weresuspended in this liquid while being mixed with a magnetic stirrer toprepare the spraying liquid. Next, 76.16 parts of Macrogol 6000 and 400parts of PEO (POLYOX® WSR-303, The Dow Chemical Company) were introducedto a fluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.)and sizing was performed by spraying the above-mentioned spraying liquidat an inlet temperature of 25° C., spraying speed of 5 g/minute andspray/dry cycle of 20 seconds/40 seconds. After sizing, the sizedproduct was dried for 30 minutes at an inlet temperature of 40° C. toobtain the sized product of the present invention. The sized product hadan average particle diameter of 96 μm, a specific volume of 2.27 mL/g,and angle of repose of 37°. After adding and mixing 2.4 parts ofmagnesium stearate with 481.6 parts of this dry sized product, thismixture was made tableted at a tablet weight of 242 mg under a tabletingpressure of 400 kgf/punch from a 9 mm φ punch using a rotary tabletmachine (HT P-22, Hata Iron Works, Ltd.) to obtain thecontrolled-release pharmaceutical preparation (tablets) of the presentinvention. The tablets that were obtained had few variations withstandard deviation of weight being 0.6%, and uniformity of content wasalso good at a standard deviation of 1.8%.

Comparative Example 5

After coarse mixing of 10 parts of tamsulosin hydrochloride and 190parts of Macrogol 6000 with a poly bag, the mixture was pulverized witha hammer mill (Sample Mill AP-S, using 1 mm screen, Hosokawa MicronCorporation). Then 84.8 parts of Macrogol 6000 and 500 parts of PEO(POLYOX® WSR-303, The Dow Chemical Company) were added to 16 parts ofthe mixed and pulverized product and this was mixed for 10 minutes at 25rpm using a double cone-type mixer (5 L-type, Tokuju Corporation). Then3.0 parts of magnesium stearate were further added and mixed to obtain acomparative pharmaceutical preparation of the present invention. Whenuniformity of drug content of the mixed product that was obtained wasconfirmed, there was a reduction in drug content at 91.5% and a standarddeviation of 1.4%.

Comparative Example 6

First, 3.84 parts of sorbitol were dissolved in 11.36 parts of waterwhile mixing with a magnetic stirrer. Then 0.8 part of tamsulosinhydrochloride that had been pre-pulverized with a hammer mill (SampleMill AP-S, using 1 mm screen, Hosokawa Micron Corporation) weresuspended in this liquid while being mixed with a magnetic stirrer toprepare the spraying liquid. Next, 76.16 parts of sorbitol and 400 partsof PEO (POLYOX® WSR-303, The Dow Chemical Company) were introduced to afluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.) andsizing was performed by spraying the above-mentioned spraying liquid atan inlet temperature of 30° C., spraying speed of 5 g/minute andspray/dry cycle of 20 seconds/40 seconds. After sizing, the sizedproduct was dried for 30 minutes at an inlet temperature of 40° C. toobtain the sized product of the present invention. The sized product hadan average particle diameter of 110 μm, a specific volume of 2.04 mL/g,and angle of repose of 38°. Blending uniformity of the drug in the sizedproduct revealed a reduced uniformity of content at a drug content of98.2% and standard deviation of 5.4%.

INDUSTRIAL APPLICABILITY

The present invention presents a controlled-release pharmaceuticalcomposition containing a sized product, which contains a drug,polyethylene oxide of high viscosity and specific PEO size controllingagent and wherein of these three components, at least the sizecontrolling agent is uniformly dispersed in the polyethylene oxide.

By means of the present invention, it is possible to present acontrolled-release pharmaceutical composition for oral use with gooduniformity of content, particularly for low-dose drugs, and therefore,it can be used as useful pharmaceutical preparation technology that isextremely popular, particularly for controlled-release pharmaceuticalcompositions comprising polyethylene oxide of a high viscosity as thecontrolled-release base.

1. A process for making a pharmaceutical preparation for controlledrelease comprising a sized product, said process comprising: admixing adrug and a size controlling agent to form a suspension or aqueoussolution; and spraying said suspension or aqueous solution onto apolyethylene oxide having a viscosity-average molecular weight of2,000,000 or more to form a sized product, wherein said sized product isa collection of particles, each particle having an average diameter ofapproximately 60 μm to 300 μm.
 2. The process according to claim 1,wherein the size controlling agent is one or two or more selected fromthe group consisting of polyethylene glycol, hydroxypropylmethylcellulose of 2 to 15 mPa·s (2% w/v), hydroxypropylmethyl cellulose of 2to 10 mPa·s (2% w/v), and methyl cellulose of 2 to 15 mPa·s (2% w/v). 3.The process according to claim 1, wherein the amount of size controllingagent is 0.5 to 60 wt % per polyethylene oxide.
 4. The process accordingto claim 1, wherein when polyethylene glycol is selected as a sizecontrolling agent, the amount is 0.5 to 60 wt % per unit of thepharmaceutical preparation.
 5. The process according to claim 1, whereinthe amount of polyethylene oxide is 10 to 95 wt % per unit of thepharmaceutical preparation.
 6. The process according to claim 1, whereinthe amount of polyethylene oxide added is at least 70 mg per unit of thepharmaceutical preparation.
 7. The process according to claim 1, whereinthe viscosity-average molecular weight of polyethylene oxide is5,000,000 or higher.
 8. The process according to claim 1, wherein saidprocess further comprises admixing a hydrophilic base with said drug. 9.The process according to claim 8, wherein the amount of water requiredto dissolve 1 g of said hydrophilic base is 5 ml or less (20±5° C.). 10.The process according to claim 9, wherein the hydrophilic base is amember selected from the group consisting of polyethylene glycol,sucrose, and polyvinyl pyrrolidone.
 11. The process according to claim8, wherein the amount of hydrophilic base is 5 to 80 wt % per unit ofthe pharmaceutical preparation.
 12. The process according to claim 1,which further comprises yellow ferric oxide and/or red ferric oxide. 13.The process according to claim 12, wherein the amount of yellow ferricoxide and/or ferric oxide is 0.3 to 20 wt % per polyethylene oxide. 14.The process according to claim 1, wherein the amount of drug is 85 wt %or less per unit of the pharmaceutical preparation.
 15. The processaccording to claim 14, wherein the amount of drug is 10 wt % or less perunit of the pharmaceutical preparation.
 16. The process according toclaim 1, wherein the drug is tamsulosin hydrochloride.
 17. The processaccording to claim 1, which comprises essentially no organic solvent.18. The process according to claim 1, wherein the spraying is a memberselected from the group consisting of a high-shear agitation granulationmethod, a crushing (pulverization) granulation method, a fluidized bedgranulation method or device, an extrusion granulation method, atumbling granulation method or device, and a spray granulation method ordevice.
 19. The process according to claim 18, wherein the spraying is amember selected from the group consisting of a fluidized bed granulationmethod or device and a tumbling fluidized bed granulation or device. 20.The process according to claim 2, wherein polyethylene glycol is used inliquid form at 10 wt % or less, per PEO.
 21. The process according toclaim 1, wherein water is added during spraying by a process selectedfrom the group consisting of a continuous spraying method whereby wateris continuously added and an intermittent spraying method whereby adrying process and further, a shaking process are included in thegranulation process.